Abstract

Several immunotherapy clinical trials in recurrent glioblastoma have reported long-term survival benefits in 10–20% of patients. Here we perform genomic analysis of tumor tissue from recurrent WHO grade IV glioblastoma patients acquired prior to immunotherapy intervention. We report that very low tumor mutation burden is associated with longer survival after recombinant polio virotherapy or after immune checkpoint blockade in recurrent glioblastoma patients. A relationship between tumor mutation burden and survival is not observed in cohorts of immunotherapy naïve newly diagnosed or recurrent glioblastoma patients. Transcriptomic analyses reveal an inverse relationship between tumor mutation burden and enrichment of inflammatory gene signatures in cohorts of recurrent, but not newly diagnosed glioblastoma tumors, implying that a relationship between tumor mutation burden and tumor-intrinsic inflammation evolves upon recurrence.

Recurrent glioblastomas (rGBM) have dismal outcomes, but long-term survival has been observed in subsets of patients after immunotherapy. Here the authors report a positive association between low tumor mutation burden, inflammatory gene signatures, and survival after immunotherapy in rGBM patients.

Details

Title
Very low mutation burden is a feature of inflamed recurrent glioblastomas responsive to cancer immunotherapy
Author
Gromeier Matthias 1   VIAFID ORCID Logo  ; Brown, Michael C 1   VIAFID ORCID Logo  ; Zhang, Gao 1   VIAFID ORCID Logo  ; Lin, Xiang 2 ; Chen, Yeqing 2 ; Wei, Zhi 2   VIAFID ORCID Logo  ; Beaubier Nike 3   VIAFID ORCID Logo  ; Yan, Hai 4 ; He, Yiping 4 ; Desjardins Annick 1 ; Herndon, James E, II 5 ; Varn, Frederick S 6   VIAFID ORCID Logo  ; Verhaak Roel G 6   VIAFID ORCID Logo  ; Zhao Junfei 7 ; Bolognesi, Dani P 8 ; Friedman, Allan H 1 ; Friedman, Henry S 1 ; McSherry, Frances 9 ; Muscat, Andrea M 10 ; Lipp, Eric S 1   VIAFID ORCID Logo  ; Nair, Smita K 11   VIAFID ORCID Logo  ; Khasraw Mustafa 1   VIAFID ORCID Logo  ; Peters, Katherine B 1 ; Randazzo, Dina 1 ; Sampson, John H 1   VIAFID ORCID Logo  ; McLendon, Roger E 4   VIAFID ORCID Logo  ; Bigner, Darell D 1 ; Ashley, David M 1 

 Duke University Medical Center, Department of Neurosurgery, Durham, USA (GRID:grid.189509.c) (ISNI:0000000100241216); The Preston Robert Tisch Brain Tumor Center at Duke University Medical Center, Durham, USA (GRID:grid.26009.3d) (ISNI:0000 0004 1936 7961) 
 Department of Computer Science at the New Jersey Institute of Technology, Newark, USA (GRID:grid.260896.3) (ISNI:0000 0001 2166 4955) 
 Tempus Labs, Inc., Chicago, USA (GRID:grid.260896.3) 
 The Preston Robert Tisch Brain Tumor Center at Duke University Medical Center, Durham, USA (GRID:grid.26009.3d) (ISNI:0000 0004 1936 7961); Duke University Medical Center, Department of Pathology, Durham, USA (GRID:grid.189509.c) (ISNI:0000000100241216) 
 The Preston Robert Tisch Brain Tumor Center at Duke University Medical Center, Durham, USA (GRID:grid.26009.3d) (ISNI:0000 0004 1936 7961); Duke University Medical Center, Department of Biostatistics, Durham, USA (GRID:grid.189509.c) (ISNI:0000000100241216) 
 The Jackson Laboratory for Genomic Medicine, Farmington, USA (GRID:grid.249880.f) (ISNI:0000 0004 0374 0039) 
 Department of Systems Biology at Columbia University, New York, USA (GRID:grid.21729.3f) (ISNI:0000000419368729) 
 Duke University Medical Center, Department of Surgery, Durham, USA (GRID:grid.189509.c) (ISNI:0000000100241216); Istari Oncology Inc., Morrisville, USA (GRID:grid.189509.c) 
 Duke University Medical Center, Department of Biostatistics, Durham, USA (GRID:grid.189509.c) (ISNI:0000000100241216) 
10  Deakin University, School of Medicine, Geelong, Australia (GRID:grid.1021.2) (ISNI:0000 0001 0526 7079) 
11  Duke University Medical Center, Department of Surgery, Durham, USA (GRID:grid.189509.c) (ISNI:0000000100241216) 
Publication year
2021
Publication date
2021
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2477376291
Copyright
© The Author(s) 2021. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.